TY - JOUR
T1 - The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy
AU - Pena, Michelle J.
AU - de Zeeuw, Dick
AU - Andress, Dennis
AU - Brennan, John J.
AU - Correa-Rotter, Ricardo
AU - Coll, Blai
AU - Kohan, Donald E.
AU - Makino, Hirofumi
AU - Perkovic, Vlado
AU - Remuzzi, Giuseppe
AU - Tobe, Sheldon W.
AU - Toto, Robert
AU - Parving, Hans Henrik
AU - Sharma, Shoba
AU - Corringham, Tom
AU - Sharma, Kumar
AU - Heerspink, Hiddo J.L.
N1 - Funding Information:
H. J. L. H. is supported by a VIDI grant from the Netherlands Organisation for Scientific Research. M. J. P. has no conflicts of interests. D. deZ. has consultancy agreements with the following companies: AbbVie, Astellas, Chemocentryx, Eli Lilly, Fresenius, Johnson & Johnson, Merck Darmstadt. All honoraria are paid to his institution. R. C.-R. has consultancy agreements with: AbbVie, AstraZeneca, Boehringer Ingelheim, Roche, Amgen and has been a speaker for AstraZeneca and Roche in the last 2 years. D. K. consults for AbbVie and has received grant support from the US National Institutes of Health (NIH). H. M. is a consultant for AbbVie and Teijin; he receives speaker honoraria from Astellas, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Pfizer, Takeda and Tanabe Mitsubishi; and he receives grant support from Astellas, Boehringer Iingelheim, Daiichi Sankyo, Dainippon Sumitomo, Kowa, Kyowa Hakko Kirin, MSD, Novartis, Novo Nordisk, Ono, Otsuka, Pfizer, Taishyo-Toyama, Takeda, Teijin and Tanabe Mitsubishi. S. T. consults for AbbVie. H.-H. P. consults for AbbVie. R. T. is a consultant to Amgen, Boehringer Ingelheim, ZS Pharma, Bayer, Quintiles, Relypsa and receives grant support from the US NIH. V. P. consults for AbbVie, Astellas, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline and Janssen; he has received lecture fees or grant support from Baxter, Boehringer Ingelheim, Merck and Pfizer; and his institution has held clinical trial contracts with AbbVie, Roche, Janssen, Servier and Novartis. G.R. has consultancy agreements with Domp? farmaceutici S.pA., AbbVie*, Alexion Pharmaceuticals*, Bayer Healthcare*, Reata Pharmaceuticals*, Novartis Pharma*, AstraZeneca*, Otsuka Pharmaceutical Europe* and Concert Pharmaceuticals*. *No personal remuneration is accepted and compensations are paid to his institution for research and educational activities. H.J.L.H. has consultancy agreements with the following companies: AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Johnson & Johnson, Reata Pharmaceuticals and ZN-Pharma. All honoraria are paid to his institution. K. S. is the scientific founder and consultant of Clinical Metabolomics, Inc. and has an equity interest in the company. T. C. and S. S. were employees of and were paid directly by Clinical Metabolomics, Inc. at the time of this study. B. C. was employed by AbbVie at the time of the study. He is currently employed by Amgen, Inc. D. A. and J. B. are employees of AbbVie and may own stock or stock options. M. J. P. and H. J. L. H. are responsible for data analysis, interpretation and manuscript preparation. S. S., T. C. and K. S. are responsible for data analysis and interpretation. D. dZ., D. A., J. J. B., R. C.-R., B. C., D. E. K., H. M., V. P., G. R., S. W. T., R. T. and H.-H. P. contributed to study design and data collection. All authors participated in the writing, review and approval of this manuscript.
Publisher Copyright:
© 2016 John Wiley & Sons Ltd
PY - 2017/5
Y1 - 2017/5
N2 - We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2. After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2, a single-value index of the metabolites changed by −0.31 (95%CI −0.60 to −0.02; P =.035), −0.08 (−12 to 0.29; P =.43) and 0.01 (−0.21 to 0.19; P =.913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (−0.17 to 0.43; P =.40) and 0.35 (0.05-0.65; P =.02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2, suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated.
AB - We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2. After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2, a single-value index of the metabolites changed by −0.31 (95%CI −0.60 to −0.02; P =.035), −0.08 (−12 to 0.29; P =.43) and 0.01 (−0.21 to 0.19; P =.913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (−0.17 to 0.43; P =.40) and 0.35 (0.05-0.65; P =.02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2, suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated.
KW - diabetic kidney disease
KW - eGFR decline
KW - metabolomics
UR - http://www.scopus.com/inward/record.url?scp=85013371547&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85013371547&partnerID=8YFLogxK
U2 - 10.1111/dom.12864
DO - 10.1111/dom.12864
M3 - Article
C2 - 28019071
AN - SCOPUS:85013371547
SN - 1462-8902
VL - 19
SP - 749
EP - 753
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
IS - 5
ER -
